The present invention relates to aryl substituted 1,4-diazepanes having affinity at the serotonin 5-hydroxytryptamine 2C (5HT2C) receptor and functioning as agonists at that receptor. Compounds having this activity are useful for the treatment of disorders such as obsessive-compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, sexual dysfunction, obesity, and epilepsy.
Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, feeding behavior, sexual activity, and neuroendocrine regulation among others. 5-HT2C receptor ligands are believed to be of potential use in the treatment of certain central nervous system (CNS) disorders such as anxiety disorders such as generalized anxiety, obsessive-compulsive disorder, social phobias, and panic disorder; affective (i.e., mood) disorders such as depression, atypical depression and bipolar disorders; psychoses involving gross impairment of reality such as schizophrenia and related disorders; sleep disorders; eating disorders (e.g., anorexia, and bulimia); obesity; epilepsy; diabetes; and migraine. EP556889A1 reports the synthesis of arylpiperazines and arylhomopiperazines. WO99/32461 presents a scenario similar to EP556889A1 with the homopiperazine attached to the 1-position of the 1,2,3,4-tetrahydronaphthyl ring.
This invention relates to novel aryl substituted 1,4-diazepanes, such as derivatives of 6-(1,4-diazepan-1-yl)benzo[cd]indol-2(1H)-one, 6-(1,4-diazepan-1-yl)acenaphthylen-1 (2H)-one and 5-(1,4-diazepan-1-yl)-2H-naphtho[1,8-cd]isothiazole-1,1-dioxide; to processes for their preparation; to pharmaceutical compositions containing them and to their use in therapy. These compounds are believed to have affinity at the serotonin 5-hydroxytrptamine 2C (5HT2C) receptor and are believed to function as agonists at that receptor. Compounds having this activity are useful for the treatment of disorders such as anxiety disorders such as generalized anxiety, obsessive-compulsive disorder, social phobias, and panic disorder; affective (i.e., mood) disorders such as depression, atypical depression and bipolar disorders; psychoses involving gross impairment of reality such as schizophrenia; sleep disorders; eating disorders (e.g., anorexia and bulimia); obesity; epilepsy; diabetes; and migraine.
Compounds of this invention include those of Formula (1) or a non-toxic, pharmaceutically acceptable salt thereof 
where:
X is C or N;
Y is CH2, Cxe2x95x90O, Sxe2x95x90O, or SO2;
Z is N or C;
R1, R1a and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group;
R2, R3, R4, R5 and R6 are each independently selected from hydrogen, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, alkanoyl, CN, CHO, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, OCOOalkyl, OCOOaryl, OCONR18, COOH, COOalkyl, COOaryl, CONR18R19, CONHOH, NR18R19, SO2NR18R19, NO2, NH2, or OH group, where R18 and R19 are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, perfluoroalkyl, COalkyl, COaryl, COheteroaryl, COOalkyl, COOaryl, COOheteroaryl, CONHalkyl, CON(alkyl)2, CONHaryl, CONHheteroaryl, cycloalkyl, cycloheteroalkyl, S(O)m-alkyl or S(O)m-aryl group, where m is 0, 1 or 2;
R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl or heteroaryl group; and
where p is 1 when X is carbon and p is zero when X is nitrogen.
Preferred compounds of the present invention are represented by the general Formula (II) or a pharmaceutically acceptable salt thereof. 
where:
X is either C or N;
Y is either CH2, C(O) or SO2;
R1, R1a, and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, or alkenyl group; and
R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are dedined as before.
A second preferred class of compounds of the present invention is represented by Formulas (III) or (IV), or a pharmaceutically acceptable salt thereof: 
where
R1 and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are defined as before.
A third preferred class of compounds of the present invention is represenited by Formulas (V) or (VI), or a pharmaceutically acceptable salt thereof: 
where:
R1, R1a and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are defined as before.
A fourth preferred class of compounds of the present invention is represented by Formulas (VII) or (VIII), or a pharmaceutically acceptable salt thereof: 
where:
R1, R1a and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are defined as before.
A fifth preferred class of compounds of the present invention is represented by Formulas (IX) or (X), or a pharmaceutically acceptable salt thereof 
where:
R1 and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are defined as before.
Within each of the classes of compounds of Formulas (I) through (X), it is preferred that the moiety: 
where R21, R22, and R23 are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl or heteroaryl group, and R11 is defined as before for each formula.
In another embodiment of Formulas (I) through (X), the variables R7, R8, R9, R10 R12, R13, R14, R15, R16 and R17 are preferably hydrogen and R11 is defined as before for each formula.
In another embodiment of Formulas (I) through (X), the variables R2, R3, R4, R5 and R6 are each hydrogen and R1 and R7 through R17 are as defined before for each formula.
Compounds of the invention include those of Formula (I) or a non-toxic, pharmaceutically acceptable acid addition salt thereof 
where:
X is C or N;
Y is CH2, Cxe2x95x90O, Sxe2x95x90O, or SO2;
Z is Cor N;
R1, R1a, and R11 are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group;
R2, R3, R4, R5 and R6 are each independently selected from hydrogen, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, alkanoyl, CN, CHO, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, OCOOalkyl, OCOOaryl, OCONR18, COOH, COOalkyl, COOaryl, CONR18R19, CONHOH, NR18R19, SO2NR18R19, NO2, NH2, or OH group, where R18 and R19 are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, perfluoroalkyl, COalkyl, COaryl, COheteroaryl, COOalkyl, COOaryl, COOheteroaryl, CONHalkyl, CON(alkyl)2, CONHaryl, CONHheteroaryl, cycloalkyl, cycloheteroalkyl, S(O)m-alkyl or S(O)m-aryl group, where m is 0, 1 or 2;
R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl or heteroaryl group; and where p is 1 when X is carbon and p is zero when X is nitrogen.
As used in connection with Formulas (I) through (X):
xe2x80x9calkylxe2x80x9d is defined as a C1-8 alkyl group, that may optionally be substituted with one to three groups independently selected from R20;
xe2x80x9cR20xe2x80x9d is hydrogen, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, alkanoyl, CN, CHO, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, OCOOalkyl, OCOOaryl, OCONR18, COOH, COOalkyl, COOaryl, CONR18R19, CONHOH, NR18R19, SO2NR18R19, NO2, NH2, OH, S(O)m-alkyl or S(O)m-aryl group, where m is 0, 1 or 2, R18 and R19 are defined as in Formula (I), and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, OCOOalkyl, OCOOaryl, COOalkyl, COOaryl, S(O)m-alkyl and S(O)m-aryl groups may be optionally substituted with one or more halogens (referred to hereinafter as xe2x80x9chalogenatedxe2x80x9d);
xe2x80x9calkenylxe2x80x9d is defined as a C3-10 alkenyl group having 1 to 2 double bonds, that may be optionally substituted with one to three groups independently selected from R20;
xe2x80x9calkynylxe2x80x9d is defined as a C3-10 alkynyl group having 1-2 triple bonds, that may be optionally substituted with one to three groups independently selected from R20;
xe2x80x9carylxe2x80x9d is defined as 
optionally substituted with one to three groups independently selected from R20,
xe2x80x9carylalkylxe2x80x9d is a type of alkyl (where one R20 is aryl) or aryl (where one R20 is alkyl) as defined above that contains at least one alkyl group and at least one aryl group, that may optionally be substituted on the aryl and/or alkyl portion of the arylalky with one to three groups independently selected from R20; examples include methoxybenzyl, phenylethyl, or phenylpropyl;
xe2x80x9ccycloalkylxe2x80x9d is defined as C3-8 cycloalkyl, optionally substituted with one to three groups independently selected from R20 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl;
xe2x80x9ccycloheteroalkylxe2x80x9d is defined as 
where T is defined as NR18, O, or S (R18 being defined the same as in Formula (I)), and where each cycloheteroalkyl group may optionally be substituted with one to six groups independently selected from R20; it being understood that a carbon of the cycloheteroalkyl may optionally be double bonded to either O or S to form for example, a lactam or urea;
xe2x80x9cheteroarylxe2x80x9d is defined as 
where T is defined as before and where each heteroaryl moiety is optionally substituted with one to three groups independently selected from R20; and
xe2x80x9chalogenxe2x80x9d is defined as fluorine, chlorine, bromine or iodine.
xe2x80x9cPharmaceutically acceptable salt(s)xe2x80x9d, as used herein, are the acid addition salts which can be formed from a compound of Formulas (I) through (X) and a pharmaceutically acceptable acid such as, for example, phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic acid. By the term xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
Preferred compounds include those of Formula (I) where:
Z is N;
Y is Cxe2x95x90O or SO2;
R1 and R1a are independently selected from hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, C1 to C3 alkoxy groups, halogenated C1 to C3 alkoxy groups or combinations thereof, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups or halogenated alkoxy C1 to C3 groups, or a C3 to C10 alkenyl group; and more preferably are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, phenylethyl, phenylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, or allyl;
R11 is selected from hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, C1 to C3 alkoxy groups, halogenated C1 to C3 alkoxy groups, CN, COOalkyl, COOaryl or combinations thereof, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups or halogenated C1 to C3 alkoxy groups, or a C3 to C10 alkenyl group; and more preferably is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, trifluoromethoxybenzyl, nitrobenzyl, phenylethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclohexyl, allyl, methylallyl, 3,7-dimethylocta-2,6-dienyl, ethoxyethyl, cyanomethyl, cyanobutyl, ethoxycarbonylmethyl, benzyloxycarbonyl methyl;
at least two of R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are hydrogen and more preferably each of R7, R8, R9, R10, R12, R13, R14, R15, R16, and R17 are hydrogen; or
at least two of R2, R3, R4, R5 and R6 are hydrogen and more preferably each of R2, R3, R4, R5 and R6 are hydrogen; or
any combination of the above preferred variables for Formula (I).
In another preferred embodiment of the present invention R1 and R1a are the same when X of Formula (I) is carbon.
Preferred compounds of the present invention also include those compounds of Formulas (II) through (X) previously defined herein.
Further, with respect to Formulas (III) and (IV), in a preferred embodiment R1 is hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups, or a C3 to C10 alkenyl group, and more preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, phenylethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, or allyl. R11 is preferably hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups or C1 to C3 halogenated alkoxy groups, or a C3 to C10 alkenyl group, and more preferably hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, trifluoromethoxybenzyl, nitrobenzyl, phenylethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl.
With respect to Formulas (V), (VI), (VII) and (VIII), in a preferred embodiment R1 and R1a are independently selected from hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, or a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups, and more preferably are independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, or cyclohexylmethyl. R11 is preferably hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups or C1 to C3 halogenated alkoxy groups, or a C3 to C10 alkenyl group, and more preferably is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, trifluoromethoxybenzyl, nitrobenzyl, phenylethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclohexyl, allyl, methylallyl, or 3,7-dimethylocta-2,6-dienyl.
With respect to Formulas (IX) and (X), in a preferred embodiment, R1 is hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups, or a C3 to C10 alkenyl group, and more preferably is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, phenylethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, or allyl. R11 is preferably hydrogen, an unsubstituted linear or branched saturated C1 to C6 alkyl group, a C1 to C6 linear or branched saturated alkyl group substituted with one to three halogens, C1 to C3 alkoxy groups, CN, COOalkyl, COOaryl or combinations thereof, an unsubstituted C3 to C6 cycloalkyl group, a C3 to C6 cycloalkyl group substituted with one to three C1 to C3 alkyl groups, an unsubstituted phenyl C1 to C3 alkyl group, a phenyl C1 to C3 alkyl group substituted with one to three C1 to C3 alkoxy groups or C1 to C3 halogenated alkoxy groups, or a C3 to C10 alkenyl group, and more preferably is methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluorobutyl, trifluoropropyl, benzyl, methoxybenzyl, trifluoromethoxybenzyl, nitrobenzyl, phenylethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclohexyl, allyl, methylallyl, 3,7-dimethylocta-2,6-dienyl, ethoxyethyl, cyanomethyl, cyanobutyl, ethoxycarbonylmethyl, or benzyloxycarbonylmethyl.
Compounds of the present invention may be prepared by those skilled in the art of organic synthesis using methods disclosed herein, which utilize readily available reagents and starting materials. While the synthesis methods disclosed herein provide specific synthesis examples, one skilled in the art of organic synthesis will be able to produce a variety of compounds falling under Formula (I), based on these synthesis examples in combination with techniques known to those skilled in organic synthesis.
The 4-(homo)piperazinyl isobenzylindoles of the present invention may be synthesized, for example, by the reaction scheme shown below.
In this reaction scheme, the reaction of isobenzoindole (2) and bromine gives the corresponding 4-bromo-isobenzoindole (3). Compound (3) can then be alkylated using different alkyl iodides to give N-alkylated 4-bromo-isobenzoindole (4). Compound (4) can in turn be coupled with (homo)piperazine or piperazine like compounds using a palladium catalyst to give the 4-piperazinyl-isobenzoisoindole (5). Alkylation of compound (5) using an alkyl iodide gives the final compound (6). 
One skilled in the art would recognize that compound 6 above could, for example, be further reduced to convert the Cxe2x95x90O moiety to CH2 to produce compounds of Formula (IX).
(Homo)piperazinyl sultam derivatives may, for example, be synthesized via the reaction scheme below starting with a sultam compound (7). Alkylation of brominated sultam (8) can be carried out using Mitsunobu conditions (triphenyl phosphine, alcohol, and di-tert-butyl azodicarboxylate, i.e. DBAD). 
Compounds of Formula (III) could be synthesized, for example, from compound 11 above by reducing the SO2 group to SH and then oxidizing SH using conventional techniques to produce Sxe2x95x90O.
Compounds of Formula (VIII) may be synthesized, for example, via the reaction scheme shown below. In this reaction scheme below, the corresponding bromoacenaphthenone (14) is prepared from 1-xcex1-naphthylacetic acid (12) through Friedal-Craft reaction and followed by a bromination. Compound (14) was next subjected to alkylation and palladium catalyzed amination similar to that described earlier for compound (4). 
Compounds of Formula (VII) could be produced, for example, by reducing the Cxe2x95x90O moiety of compound (17) to CH2 using techniques well known to those skilled in the art.
Intermediates to compounds of Formula (VI) could be produced, for example, via the following reaction scheme: 
Compound (22) could then, for example, be brominated and coupled with (homo)piperazine or a piperazine like compound using a palladium catalyst in accordance with procedures previously described herein to produce a compound of Formula (VI).
Alternatively, compound (22) could be produced via the following reaction scheme and then converted to a compound of Formula (VI) as previously described. 
Further examples of synthesizing compounds of Formula (I) are provided hereinafter in the Examples.
The compounds of Formula (I) are 5HT2C agonists as evidenced by standard pharmacological test procedures. The 5HT2C receptor agonists of this invention are useful for the treatment or prevention in mammals, preferably in humans, of disorders involving the central nervous system. These disorders may be organic or psychological based. Examples of central nervous system disorders affected by the 5HT2C receptor include psychoses involving gross impairment of reality such as schizophrenia, schizoaffective disorder, schizophreniform disorder, or L-DOPA-induced psychosis; disorders of the personality; affective disorders (i.e., mood disorders) such as depression, atypical depression, and bipolar disorders; drug and alcohol addiction, including disorders related to withdrawal from drug or alcohol; sleep disorders (e.g., sleep apnea); eating disorders (e.g., hyperphagia, bulimia or anorexia nervosa); obesity, including consequent comorbidities such as Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality; diabetes; intellectual deficit disorders such as dementia, Alzheimer""s disease, and memory deficit; migraines; epilepsy; sexual dysfunction; and premenstrual tension. The term xe2x80x9cdisorders of the personalityxe2x80x9d as used herein are meant to include mental disorders involving inflexible and/or maladaptive personality traits and result for example in significant impairment in social functioning. Personality disorders include for example aggressivity; and anxiety disorders such as obsessive-compulsive disorder, panic disorder, generalized anxiety, and social phobias. The compounds of the present invention may be used to treat or prevent one or more of these mental disorders present in a mammal.
The present invention also includes methods of utilizing the compounds herein in treatments or preventative regimens for treatment of central nervous system deficiencies associated, for example, with trauma, stroke, spinal cord injuries, neurodegenerative diseases, toxic or infective CNS ailments including, but not limited to, encephalitis or meningitis; cardiovascular disorders such as thrombosis; or gastrointestinal disorders, such as malfunction of gastrointestinal motility. These methods include the improvement or inhibition of further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.
The present invention provides methods for treating, preventing, inhibiting or ameliorating each of these conditions, the methods comprising administering to a mammal in need thereof a pharmaceutically or therapeutically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for treating conditions related to or are affected by the 5HT2C receptor that includes administering to warm-blooded animals, including humans, an effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof.
A pharmaceutically or therapeutically effective amount of the compounds herein is understood to comprise an amount of the compound(s) in question which will obtain at least a minimum of desired effect in preventing, treating, inhibiting or managing the symptoms or causes of the malady in question. More preferably, the amount will be the minimum needed to alleviate or remove the undesirable physiological consequences of the malady in question and inhibit or prevent their re-occurrence.
The compounds of the present invention may be formulated into pharmaceutical compositions. These pharmaceutical compositions may be administered to mammals in accordance with the methods of the present invention.
Pharmaceutical compositions, in addition to containing a pharmaceutically effective amount of one or more compounds of the present invention, may include one or more ingredients known to those skilled in the art for formulating pharmaceutical compositions. Such ingredients include for example, carriers (e.g., in solid or liquid form), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, encapsulating materials, emulsifiers, buffers, preservatives, sweeteners, thickening agents, coloring agents, viscosity regulators, stabilizers or osmo-regulators. The pharmaceutical compositions may be in solid form (e.g., powder or tablet) or in liquid form.
Solid pharmaceutical compositions preferably contain one or more solid carriers, and optionally one or more other additives such as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes or ion exchange resins, or combinations thereof. In powder pharmaceutical compositions, the carrier is preferably a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions, and optionally, other additives, and compacted into the desired shape and size. Solid pharmaceutical compositions, such as powders and tablets, preferably contain up to 99% of the active ingredient.
Liquid pharmaceutical compositions preferably contain one or more compounds of the present invention and one or more liquid carriers to form solutions, suspensions, emulsions, syrups or elixirs. Pharmaceutically acceptable liquid carriers include water, organic solvent, pharmaceutically acceptable oils or fat, or combinations thereof. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Pharmaceutical compositions for oral administration may be either in liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, such as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient. The unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The pharmaceutically or therapeutically effective dosage to be used in the treatment of a specific ailment must be subjectively determined by the attending physician. The variables involved include the specific ailment, and the size, age and response pattern of the patient. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition treated. The usual daily dose is 0.01-1000 mg/Kg , preferably 0.5-500 mg/Kg for oral application, and 0.1-100 mg/Kg, preferably 0.5-50 mg/Kg for parenteral application.